Late onset Alzheimer's disease (LOAD) is a chronic neurodegenerative disorder that typically manifests clinically in the elderly. Interestingly, a variety of postmortem evidence suggests that the pathological hallmarks of AD, and by inference the disease itself, begin to occur early in an individual's life. This has led to an emerging view of LOAD whereby a set of disparate mechanistic triggers over a life-time converge upon shared biochemical pathways to elicit a phenotypically similar clinical syndrome and neuropathological state. This convergent pathophysiological hypothesis asserts that specific downstream biochemical pathways mediate the synaptic loss, cellular injury, and death observed in LOAD. Furthermore, many of these pathophysiological changes will be manifest in peripheral systems, which share these signaling pathways. We hypothesize that the hematopoietic system shares many cellular signaling pathways with the nervous system and is affected by many of the same pathophysiological changes that characterize LOAD. Specifically, we propose that peripheral leukocytes are affected by LOAD pathogenic processes, which will be reflected m alterations in protein levels and functions. As such, these changes will serve as important biomarkers for LOAD diagnosis and progression and will provide valuable insights into its pathophysiology and potential therapeutics. Our Specific Aims will test the following hypotheses using both exploratory and directed proteomics approaches in two cohorts of well-characterized, age-matched subjects with and without LOAD. Aim 1; Exploratory proteomics approaches will identify unique protein profiles in peripheral leukocytes in LOAD subjects compared to non-LOAD subjects. Hypothesis: Quantitative protein profiling in leukocytes will identify profiles of proteins that will identify LOAD subjects from age- and gender-matched non-demented control, non-demented Parkinson's disease, and mild cognitive impairment (MCI) subjects. Aim 2: Directed proteomics approaches will validate these biomarkers and will classify subjects with LOAD from non-LOAD subjects. Hypothesis: Directed Proteomics methods (Western blots, immunoprecipitation Western blots, ELISAs, activity assays) will validate our biomarker set in the first cohort of subjects and will classify LOAD from non-demented control subjects in a second cohort. Taken together, these studies will identify a unique set of leukocyte proteins that will differentiate LOAD from non-LOAD subjects and will provide important information on the diagnosis, progression, pathophysiology, and potential therapies for LOAD.